Helping New Drugs Out of Research’s ‘Valley of Death’

The first is the number of medical research papers that were published in 2008. The second is the number of new drugs that were approved by the Food and Drug Administration last year.

An ocean of research is producing cures and treatments by the drop.

That’s an ocean of research producing treatments by the drop. Indeed, in recent decades, one of the most sobering realities in the field of biomedical research has been the fact that, despite significant increases in funding — as well as extraordinary advances in things like genomics, computerized molecular modeling, and drug screening and synthesization — the number of new treatments for illnesses that make it to market each year has flatlined (pdf) at historically low levels.
And before anyone jumps to pin the blame on the F.D.A., it’s important to note that it’s not just new drug approvals that have declined — new drug applications have, too. Last year the F.D.A. received just 23. This situation has prompted researchers to question the productivity of the system that is supposed to turn biological knowledge into cures.

In Fixes, we have explored how systems can be made to work better when people come together to focus on common goals and deliberately align their efforts. We’ve looked at how “cradle-to-career” collaboration can produce gains in education. We’ve seen how a targeted and methodological approach can reduce chronic homelessness far more quickly than anticipated.

A handful of groups are getting involved in actively managing the creation of new cures.

The M.R.F. was founded by Scott Johnson, 55, who was diagnosed with MS when he was 20. MS is a chronic condition that occurs when the body’s immune system goes awry, and attacks myelin in the central nervous system and brain (myelin insulates neural axons and is necessary to keep them healthy and signaling properly.) Nobody knows what causes MS. Symptoms accumulate over time and the disease progresses at different rates in different people. For Johnson, the main effect has been to cause a loss of mobility on much of the right side of his body. “I don’t have any cognitive issues, knock on wood,” he says.

Before founding the M.R.F. in 2004, Johnson spent decades in business, initiating new ventures in large companies and taking startups public. Ten years ago, he came across an item in a business magazine that talked about new possibilities for myelin repair. In the late 1990s, neurologists were gaining insight into the “plasticity” of the central nervous system and its potential for regeneration. Today, treatments for MS work by suppressing the immune system’s damage to myelin; the idea that myelin could potentially be repaired — and that damage caused by MS could be reversed — was new and exciting.

Johnson called up scientists to learn more and to see how he could help. He learned that little money or attention was being directed to myelin repair. He thought that he could have an impact simply by bringing in some new funding. But the more he spoke with researchers, the more he came to understand that the problem wasn’t just money. “During those interviews,” he told me, “I discovered how the system was broken.”

Here’s what he learned. The primary mechanism for getting funding for biomedical research is to write a grant proposal and submit it to the N.I.H. or a large foundation. Proposals are reviewed by scientists, who decide which ones are most likely to produce novel discoveries. Only a fraction get funded and there is little encouragement for investigators to coordinate research with other laboratories. Discoveries are kept quiet until they are published in peer-reviewed journals, so other scientists learn about them only after a delay of years. In theory, once findings are published, they will be picked up by pharmaceutical companies. In practice, that doesn’t happen nearly as often as it should.

The explosion in biomedical sciences has made it virtually impossible for industry researchers to keep up. In 2010, more than 3,000 articles were published on MS alone, explained Tassie Collins, an immunologist who directed drug discovery at the biotech firm Amgen before she joined the M.R.F. “Information on a target [usually a protein that is implicated in a key biological process] gets published, and then it just lays there in what’s called the ‘valley of death.’ It’s like in “Horton Hears a Who” — you’re trying to find the little puffball that the Whos live on.”

In contrast to academics, industry researchers operate on tight schedules driven by their companies’ annual reporting requirements. “You have a lot of pressure to go as fast as you possibly can,” adds Collins. “What that means is it’s very difficult for an industry scientist to do a deep dig in any direction.” At Amgen, Collins had to keep tabs on six diseases.

But even when promising discoveries come to the attention of pharmaceutical researchers, the companies won’t invest in them on the basis of a single publication. It’s too risky. “I always sort of assumed that if I made a discovery that had immediate implications for new treatment for disease, big pharma would pick up on it and do the drug development step,” explained Ben A. Barres, Professor and Chair of Neurobiology at Stanford University School of Medicine, whose lab works with the M.R.F. “That’s infrequently the case. Usually things just sort of languish.”

What’s missing? For a discovery to reach the threshold where a pharmaceutical company will move it forward what’s needed is called “translational” research — research that validates targets and reduces the risk. This involves things like replicating and standardizing studies, testing chemicals (potentially millions) against targets, and if something produces a desired reaction, modifying compounds or varying concentration levels to balance efficacy and safety (usually in rats). It is repetitive, time consuming work — often described as “grunt work.” It’s vital for developing cures, but it’s not the kind of research that will advance the career of a young scientist in a university setting.

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“Pure science is what you’re rewarded for,” notes Dr. Barres. “That’s what you get promoted for. That’s what they give the Nobel Prizes for. And yet developing a drug is a hundred times harder than getting a Nobel Prize. We really have to have the very best scientists engaged in this. For a long time this hasn’t been the case. Until five or ten years ago, working on disease was kind of shunned.”

Pharmaceutical companies are less inclined to fund translational research when others own the intellectual property. So while discoveries fall into the ‘valley of death,’ companies find their pipelines of drug candidates drying up. To generate profits, big pharma has come to depend on “me too” drugs — modifications of existing medications that render them marginally safer or more effective.

It made no sense to Johnson to throw money into this system without addressing the problems. So he raised funding and spent two years laying the groundwork for a different approach — one that could increase the likelihood of success. Since MS involves the brain, immune system, and central nervous system, there is much to be gained by having neurologists, neuroscientists and immunologists work in teams. But researchers are typically wary of sharing ideas beyond their labs out of fear that someone could beat them to publication.

Johnson is a compelling person — persuasive, humble and relentless. It’s hard to imagine an organization like M.R.F. coming into existence without someone of his dedication at the helm. Over the past six years, he has done something remarkable: formed genuinely collaborative partnerships with the leading scientists whose work bears on myelin repair. He’s spent a great deal of time cultivating trust, so they feel safe sharing information. And he and his team have raised $43 million and, so far, spent about $20 million on research that aligns with its therapeutic goals.

Researchers in the foundation’s four partner labs say that the relationship hasn’t constrained their science; it’s improved it. “We are certainly looking for targets to enhance the reparative potential of the central nervous system,” explained Brian Popko, the Associate Chair for Research in the Department of Neurology at the University of Chicago. “But we weren’t encouraged to develop therapeutic approaches before we understood the system we were trying to repair.”

Johnson has also assembled some of the country’s most accomplished neurologists and immunologists, as well as industry experts to sit on M.R.F.’s three advisory boards, which focus, respectively, on basic science, drug discovery and clinical issues.

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To date, researchers have identified a number of targets, of which five to seven are strong candidates that M.R.F. is actively pursuing. They are in close contact with industry researchers and will be farming out the “translational” research needed to attract pharmaceutical interest. They control 50 percent of the licensing of patents for research they fund and, as a nonprofit, can be very flexible in negotiating fees. Within five years, Johnson envisions partnerships with four or five companies, each of which will be moving a couple of targets forward. “We hope to have our first clinical trial for myelin repair by 2014,” he says. “To get to a clinical trial within ten years in an area of research that until recently no one thought was therapeutically relevant would be hugely significant.”

If the M.R.F., and like-minded foundations, succeed, their models will likely influence the bigger actors in medical research. Francis S. Collins, the head of the N.I.H., is pushing to create a new drug development center to be named the National Center for Advancing Translational Sciences.

A question that will arise is whether drug development can be advanced more effectively by the government or by nimble foundations like the M.R.F., whose advantage comes from the sharpness of their focus. M.R.F. doesn’t focus only on MS; it focuses only on repair strategies to treat it. This laser focus has made it possible for the foundation to become, in just six years, a single point of entry for leading research in its field — which makes it extremely useful for pharmaceutical companies.

“The system that has evolved unfortunately isn’t producing what we need. Almost everyone we’ve interacted with would love to see change — but they don’t know what that change could look like,” says Johnson. “This model makes common sense. But implementing it is a daily management challenge, because all the natural momentum is to go back and do things the way you were doing them before.”

On Friday, I’ll respond to comments, get into some of the details of how the M.R.F’s scientists collaborate, and talk about some of the implications for training young academic scientists.